The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerve bundle of the patient, and more particularly to techniques for treating painful syndromes in patients by selective electrical stimulation of vagus nerve afferent fiber activity with an implanted neurostimulating device.
The most commonly experienced form of pain may be defined as the effect of a stimulus on nerve endings, which results in the transmission of impulses to the cerebrum. This important somatic sensation and normal function of pain, referred to as nociception or nociceptive pain, informs the organism of impending tissue damage. Somatic and visceral free nerve endings, termed nociceptors, initially process such pain signals. A pathway for nociceptive pain exists within the central nervous system (CNS) through three orders of neurons, the basic excitable cell units of the nerve tissue in the nervous system. Each neuron transmits impulse information regarding the stimulus on the nerve endings along portions of the pathway.
Certain types of pain, however, including neuropathic pain and psychogenic pain, may develop without actual impending tissue damage. The term "neuropathic" relates to any disease of the nervous system and implies an underlying disease process or injury, in contrast, for example, to "neurogenic" which refers to commencing from or being caused by the nervous system. Neuropathic pain typically occurs following injury to elements of the nervous system involved in nociception, such as peripheral nerve injury, in which the lesions deafferent (i.e., remove the afferent or incoming signal fiber functions of) the nociceptive pathway, and the resultant pain is sometimes called deafferentation pain. Deafferentation is the state of loss of afferent input as occurs following peripheral nerve injury or peripheral neuropathies.
The nociceptive pathway exists for protection of the organism (such as the pain experienced in response to a burn), being inactive unless there is danger to the organism, and begins with peripheral receptors being activated. The signal travels up the peripheral nerve and into the spinal cord where synapses are made on second order neurons, which then transmit the pain signal up the spinal cord in the spinothalamic tract ending in the thalamus. Most authorities believe that pain is recognized or perceived in the thalamus. The ventrolateral and ventromedial thalamic nuclei project to the cortex where the pain is then processed with regard to localization and other integrative characteristics.
On the other hand, the neuropathic or psychogenic pain pathways are not associated with immediate action to prevent injury. The pain experienced following amputation of a limb, for example, is neuropathic--there is no danger of injury to the missing limb. Psychogenic pain is a chronic condition of pain without definite organic pathology.
By way of further exploration of the anatomy or mechanism of pain, the nerves themselves are composed of thousands of fibers of different sizes, classified by groups A, B and C. A and B fibers include axons having a myelin sheath, i.e., are myelinated, whereas the C fiber axons are unmyelinated. Axons of the A group are divided into subgroups alpha (.alpha.), beta (.beta.), gamma (.gamma.) and delta (.delta.). The pain signals originate from peripheral neural receptors, i.e., sensory nerve endings responsive to stimulation, usually from free nerve endings in the skin or the organs. When activated, a graded receptor potential is generated which causes the axon to fire action potentials. These are electrical impulses which self-propagate in a series of polarizations and depolarizations transmitted down the axon. It is not clear whether specific pain fibers exist or the sensation of pain lies in the recognition of a pattern of impulses, but in any case the pain sensations are usually carried by small diameter A.delta. fibers or C fibers. The receptor potential varies in amplitude initially and with time and may dissipate rapidly despite a continuing stimulus, with a consequent reduction in the firing frequency in the nerve fiber.
The cell body of a sensory neuron lies in the dorsal (posterior) root ganglion. The central process of the dorsal root ganglion cells enters the dorsal root and ascends and descends via the pathway of axons known as the tract of Lissauer up to 3 or 4 dermatome levels. Synapses for transmission of impulses between these first order neurons and second order neurons are made in the dorsal horn of the spinal cord, especially the substantia gelatinosa. The second order neurons then send their processes to the contralateral spinothalamic tract in the ventral (anterior) lateral aspect of the spinal cord. In an ascending pathway, the axons travel in the spinothalamic tract upward to the thalamus where they synapse on third order neurons in the ventral posterolateral nucleus of the thalamus (or posteromedial, for sensation from the face). From there, projections (processes) are formed with a variety of cortical and subcortical structures.
There is also a descending pathway which inhibits the incoming pain signals, and is therefore important in the body's own, i.e., endogenous, control of pain. This system includes the periaqueductal grey, the dorsal raphe nuclei, locus ceruleus, and nuclei of the medullary reticular formation. The nuclei send descending axons in the dorsolateral funiculus and synapse in the dorsal horn of the spinal cord. Spontaneous activation of these pathways, some of which involve activation of the endogenous opiate system, tends to suppress pain transmission.
In addition to these central connections, it has been theorized that other projections from the periphery may help to gate pain. The gate theory of pain, for example, postulates that the large diameter sensory fibers inhibit incoming small diameter fiber signals, e.g., that pain transmission is inhibited with the activation of large diameter A afferents which are activated by vibration. This is the reason one shakes his or her hand when it is burned. It is also the basis for the transcutaneous electrical nerve stimulation (TENS) analgesia, a non-invasive procedure in which electrical impulses from an external stimulator unit are applied through electrodes placed on the skin to reduce the transmission of pain signals to the brain.
Some pain syndromes are associated with overactivity of the sympathetic nervous system which occurs following peripheral nerve injury. The resulting pain and sympathetic activity is termed causalgia. Some evidence exists that norepinephrine, one of the transmitters of the sympathetic system, may excite nociceptive fibers and lead to this abnormal pain. Conversely, it may be that aberrant nerve transmission results in activation of sympathetic afferents and leads to overactivity.
The sensation of pain is subjective. The clinical reaction differs from patient to patient, and the patient's interpretation of the sensation and its potential sources may lead to apprehension and distress that exceeds or exacerbates the pain itself. It has been theorized that concentrations of excitatory and inhibitory neurotransmitters in the spinal cord and the brain may vary from individual to individual in response to different stimuli, and may be part of the basis for differences in the tolerance for pain among individuals, and even in the same individual over time. In any event, the tolerance for or threshold of pain is a dynamic process which depends on the organism's state. For example, minimal pain may be experienced in certain injuries suffered by soldiers in battle.
Diagnosis by the physician of the site and nature of the underlying pathology of pain depends almost entirely on historical information provided by the patient regarding its location, the extent that it tends to radiate, its intensity, whether it is continual or recurring, the conditions or medications which tend to reduce or increase its severity, and various other factors. This is complicated by the fact that different patients may describe pain and its apparent sources in vastly different ways, or be virtually unable to describe it adequately as to specific site or nature. The prescription of proper treatment, of course, depends on an understanding of the underlying organic basis of the pain, and is particularly difficult with those patients who experience chronic pain syndromes.
Persistent pain may, despite careful examination and investigation, lack apparent anatomical cause or be of uncertain nature. The patient may be experiencing post herpetic pain, or pain resulting from a central engram. In post-herpetic neuralgia, the sensory ganglion associated with the dermatome from which the pain is referred may be destroyed and yet the pain persists. The theory is that other areas of the nervous system are involved in the generation of pain. Chronic pain seems to burn in a pathway or engram which, when activated, reproduces the pain even in the absence of sensation to touch or pin prick in the area in which the pain seems to occur.
Common complaints include existence of spinal pain, usually in the cervical or lower spine, headache, facial pain, neck pain, and pain in the extremities. Chronic pain which lacks pathological basis is psychogenic, and may be symptomatic of patients suffering from tension, anxiety, depression, hysteria, hypochondria, or simply malingering. Persistent or recurring pain may instead be neuropathic, attributable to a carefully diagnosed condition such as arthritis, peripheral nerve pain such as causalgia, or peripheral neuropathy, for which treatment by analgesics and local anesthetic injections is often prescribed. Hyperpathia and hyperalgesia patients suffer excessive painful reaction to what may be characterized as normal pain sensations in most individuals.
An inability to diagnose an underlying pathological cause does not make the pain less real, and, for many chronic pain sufferers, it may be debilitating or disabling. The psychological effect of chronic pain is a complicating factor. With time, persistent pain may tend to take on greater, rather than less significance as in the case of most sensory stimuli. Fear associated with constant or intermittent pain may raise the specter of life-threatening disease, with consequent anxiety, irritability, insomnia, and depression. Conversely, individuals suffering from anxiety, depression or other psychological disorder may experience resultant pain syndromes.
Drug therapy is the principal form of treatment for pain today, including widespread use of analgesics, corticosteroids, antidepressants, topical anesthetics and local anesthetic injections. In an acute setting, such as after surgery, narcotics and anti-inflammatory drugs are used. For chronic pain, narcotics are generally avoided as a prescribed treatment, in favor of anti-inflammatory drugs. Other drug therapies include tricyclic antidepressants which help to activate some of the descending pathways that provide analgesia. In some cases, local or systemic administration of anesthetic agents are used. For patients with intractable pain, especially cancer patients, opiates have been delivered to the cerebrospinal fluid at programmed times by means of external drug pumps.
As noted above, TENS analgesia has been useful in controlling pain. Such treatment is most useful for pain following peripheral nerve injury (deafferentation) or back pain which is chronic and refractory to surgical therapy or in cases where surgery is not indicated. Other therapies that involve central stimulation include dorsal column stimulation and CNS stimulation. Dorsal column stimulation requires implantation of electrodes in the dorsal column of the spinal cord where, it is presumed, activation of these fibers helps to suppress incoming pain signals. The dorsal columns originate from the large (AB) fibers, the same fibers that are activated by TENS units. CNS stimulation usually involves the periaqueductal grey in the midbrain. Stimulation of the periaqueductal grey activates descending inhibitory pathways, and analgesia is blocked by opiate antagonists.
In rare situations, ablative procedures have been used to control chronic pain by interrupting the afferent pain pathways. The peripheral root may be cut to block incoming fibers. The ventral lateral aspect of the cord that contains spinothalamic fibers may be lesioned. In some cases, sectioning of the cingulate gyrus may aid in controlling pain. In cases where the pain returns, lesions may continue to be made higher up the nervous system axis. The belief is that a pain engram or memory is formed and distributed in multiple CNS sites.
In causalgia, a block of the sympathetic ganglion may reduce pain. In these cases, sympathectomy may be an effective treatment. Persons suffering from persistent and/or severe pain have also sought relief through therapies which may loosely be characterized as alternative medicine, such as acupuncture and hypnosis.
As will be discussed in greater detail below, the present invention provides improvements in therapy for alleviating chronic or persistent pain, particularly neuropathic and psychogenic pain, by electrical stimulation of the afferent fibers of the vagus nerve to modulate the electrical activity of the nerve, primarily to activate the descending anti-nociceptive pathway, to inhibit the sensation of pain.
For the moment, however, by way of further background it is noteworthy that the vagus nerve has approximately 100,000 fibers of the A, B and C classifications. Each carries electrical signal information to and from the brain. The myelinated A and B fibers are typically larger, have faster electrical conduction and much lower electrical stimulation thresholds than the unmyelinated C fibers, and exhibit a particular strength-duration curve in response to a specific width and amplitude of stimulation pulse. A and B fibers are stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. A fibers exhibit slightly faster electrical conductivities than B fibers, and slightly lower electrical stimulation thresholds. C fibers require wider pulse widths (e.g., 300-1000 .mu.s) and higher amplitudes for activation. Although the A and B fibers may be selectively stimulated without also stimulating the C fibers, the magnitude and width of the pulse required for stimulating the C fibers would also activate A and B fibers.
The vagus nerve is composed of somatic and visceral afferents (i.e., inward conducting nerve fibers which convey impulses toward a nerve center such as the brain or spinal cord) and efferents (i.e., outward conducting nerve fibers which convey impulses to an effector to stimulate it and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the skull. The central projections terminate largely in the nucleus of the solitary tract which sends fibers to various regions of the brain (e.g., the hypothalamus, thalamus, and amygdala); others continue to the roedial reticular formation of the medulla, the cerebellum, the nucleus cuneatus and other regions. Afferents activate both ascending and descending pathways.
In an article in the Journal of Neurophysiology (Vol. 50, No. 4, October 1983, at p. 926), Ammons et al. reported that left thoracic vagal nerve (LTV) stimulation depressed the background activity of 61% of the spinothalamic (ST) neurons studied in the upper thoracic cord of a study group of anesthetized monkeys. It was found that stimulation of the vagus below the heart was ineffective in ten of the thirty-two ST cells. It was concluded that LTV stimulation alters activity of ST neurons in the upper thoracic spinal cord, and that inhibition of ST cell activity could be attributed to stimulation of cardiopulmonary vagal afferent fibers coursing to the brain stem, which then appeared to activate descending inhibitory spinal pathways.
Ren et al. reported in the Vol. 64, No. 4, October 1990 issue of the Journal of Neurophysiology, on p. 1098, that vagal afferent stimulation appeared to raise the nociceptive threshold in a group of anesthetized paralyzed rats subjected to noxious thermal stimulation. The results were felt to confirm the association between vagal afferent and nociceptive systems. Other investigators have found an anti-nociceptive effect of vagal afferent stimulation by observation of the response of the tail-flick reflex in rat studies (e.g., Randich et al. in Brain Research, 445 (1988) at p. 68; Ren et al., Brain Research, 446 (1988) at p. 285; and Maixner et al., Brain Research, 298 (1984) at p. 374). This analgesic effect could be blocked by lesioning of brain stem structures important in inhibiting incoming pain signals (e.g., locus ceruleus, nucleus raphe magnus, and nucleus of the solitary tract). The anti-nociceptive effect was found to be sensitive to naloxone, an opiate antagonist. Stimulation of the nucleus of the solitary tract, which is the destination of many of the vagal afferents, also inhibits nociceptive reflexes.